The neglected CRAC proteins: Orai2, Orai3, and STIM2

Plasma-membrane-localized Orai1 ion channel subunits interacting with ER-localized STIM1 molecules comprise the major subunit composition responsible for calcium release-activated calcium channels. STIM1 "translates" the Ca(2+) store content into Orai1 activity, making it a store-operated channel. Surprisingly, in addition to being the physical activator, STIM1 also modulates Orai1 properties, including its inactivation and permeation (see Chapter 1). STIM1 is thus more than a pure Orai1 activator. Within the past 7 years following the discovery of STIM and Orai proteins, the molecular mechanisms of STIM1/Orai1 activity and their functional importance have been studied in great detail. Much less is currently known about the other isoforms STIM2, Orai2, and Orai3. In this chapter, we summarize the current knowledge about STIM2, Orai2, and Orai3 properties and function. Are these homologues mainly modulators of predominantly STIM1/Orai1-mediated complexes or do store-dependent or -independent functions such as regulation of basal Ca(2+) concentration and activation of Orai3-containing complexes by arachidonic acid or by estrogen receptors point toward their "true" physiological function? Is Orai2 the Orai1 of neurons? A major focus of the review is on the functional relevance of STIM2, Orai2, and Orai3, some of which still remains speculative.